U.S. patent application number 10/939021 was filed with the patent office on 2005-04-14 for implants with functionalized carbon surfaces.
Invention is credited to Asgari, Soheil, Ban, Andreas, Kunstmann, Jurgen, Mayer, Bernhard, Rathenow, Jorg.
Application Number | 20050079201 10/939021 |
Document ID | / |
Family ID | 32872363 |
Filed Date | 2005-04-14 |
United States Patent
Application |
20050079201 |
Kind Code |
A1 |
Rathenow, Jorg ; et
al. |
April 14, 2005 |
Implants with functionalized carbon surfaces
Abstract
The invention relates to a method of producing medical implants
having functionalized surfaces by providing a medical implant with
at least one carbon-based layer on at least one part of the surface
of the implant, activating the carbon-based layer by creating
porosity and functionalizing the activated carbon-based layer. This
invention also relates to functionalized implants obtained in by
this method.
Inventors: |
Rathenow, Jorg; (Wiesbaden,
DE) ; Asgari, Soheil; (Munchen, DE) ; Ban,
Andreas; (Koblenz, DE) ; Kunstmann, Jurgen;
(Bad Soden, DE) ; Mayer, Bernhard; (Mainz,
DE) |
Correspondence
Address: |
FROMMER LAWRENCE & HAUG
745 FIFTH AVENUE- 10TH FL.
NEW YORK
NY
10151
US
|
Family ID: |
32872363 |
Appl. No.: |
10/939021 |
Filed: |
September 10, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10939021 |
Sep 10, 2004 |
|
|
|
PCT/EP04/05785 |
May 28, 2004 |
|
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Current U.S.
Class: |
424/424 ;
424/426; 427/2.21; 427/2.24; 623/23.74 |
Current CPC
Class: |
A61L 2400/18 20130101;
A61L 27/30 20130101; A61L 27/303 20130101; A61L 2300/00 20130101;
A61L 31/082 20130101; A61L 31/146 20130101; A61L 31/16 20130101;
A61L 31/084 20130101; A61L 27/56 20130101; A61L 31/10 20130101 |
Class at
Publication: |
424/424 ;
623/023.74; 424/426; 427/002.21; 427/002.24 |
International
Class: |
B05D 003/04; A61F
002/02; B05D 003/10 |
Foreign Application Data
Date |
Code |
Application Number |
May 28, 2003 |
DE |
103 24 415.8 |
Jul 21, 2003 |
DE |
103 33 098.4 |
Jul 21, 2003 |
DE |
103 33 099.2 |
Claims
What is claimed is:
1. A method for producing medical implants having functionalized
surfaces comprising the following steps: a) providing a medical
implant with at least one carbon-based layer on at least part of
the surface of the implant; b) activating the carbon-based layer by
creating porosity; c) functionalizing the activated carbon-based
layer.
2. The method according to claim 1 wherein the carbon-based layer
is selected from pyrolytically produced carbon, vapor-deposited
carbon, carbon applied by CVD, PVD or sputtering, metal carbides,
metal carbonitrides, metal oxynitrides or metal oxycarbides as well
as any desired combinations thereof.
3. The method according to claim 1 wherein the implant consists of
a material which is selected from carbon, carbon composite
material, carbon fibers, ceramic, glass, plastics, metals, alloys,
bone, stone or minerals.
4. The method according to claim 1 wherein the implant is selected
from medical or therapeutic implants such as vascular
endoprostheses, stents, coronary stents, peripheral stents,
surgical or orthopedic implants, bone prostheses or joint
prostheses, artificial hearts, artificial heart valves,
subcutaneous and/or intramuscular implants.
5. The method according to claim 1 wherein activation of the
carbon-based layer is performed with suitable oxidizing agents
and/or reducing agents.
6. The method according to claim 1 wherein the carbon-based layer
is activated by oxidation with air, oxygen, nitrous oxide, and/or
oxidizing acids, optionally at an elevated temperature.
7. The method according to claim 1 wherein the activation is
performed by abrasion in an aqueous ultrasonic bath with the
addition of alumina, silicates and/or aluminates.
8. The method according to claim 1 wherein activation causes the
carbon-based layer to become porous, preferably macroporous with
pore diameters in the range of 0.1 to 1000 mm, optionally also by
prestructuring the substrate.
9. The method according to claim 1 wherein activation causes the
carbon-based layer to become nanoporous.
10. The method according to claim 1 wherein the activated porous
carbon-based layer is subsequently compressed and/or sealed by CVD
and/or CVI of volatile organic substances.
11. The method according to claim 1 wherein the functionalization
of the activated carbon-based layer comprises loading the layer
with at least one substance selected from pharmacological active
ingredients, linkers, microorganisms, plant or animal cells
including human cells or cell cultures and tissue, minerals, salts,
metals, synthetic or natural polymers, proteins, peptides, amino
acids, solvents, ions, cations, in particular metal cations such as
cobalt, nickel, copper, zinc cations, antibodies, calmodulin,
chitin, cellulose, sugars, amino acids, glutathione, streptavidin,
Strep-Tactin or other mutants or S protein, dextrans, as well as
their derivatives, mixtures and combinations.
12. The method according to claim 1 wherein the functionalization
is performed by adsorption of substances corresponding to affinity
tags in and/or on the carbon-based layer, whereby the corresponding
substances are selected so that they can enter into a bond with the
affinity tags.
13. The method according to claim 11 or 12 wherein the substance(s)
is/are applied to and/or immobilized on the carbon-based layer by
adsorption, absorption, physisorption, chemisorption, electrostatic
covalent bonding or non-covalent bonding.
14. The method according to claim 11 wherein the at least one
substance is essentially permanently immobilized on the
carbon-based layer(s).
15. The method according to claim 11 wherein the at least one
substance applied to the carbon-based layer, in particular a
pharmacological active ingredient, can be released from the layer
in a controlled manner.
16. The method according to claim 15 wherein the pharmacologically
active substances are incorporated into microcapsules, liposomes,
nanocapsules, nanoparticles, micelles, synthetic phospholipids, gas
dispersions, emulsions, microemulsions or nanospheres which are
adsorbed in the pores or on the surface of the carbon-based layer
and can then be released therapeutically.
17. The method according to claim 14 or 15 wherein a coating which
influences the release of the active ingredient is also applied,
selected from pH-sensitive and/or temperature-sensitive polymers
and/or biologically active barriers such as enzymes.
18. The method according to claim 1 wherein the functionalization
includes applying biodegradable and/or absorbable polymers such as
collagen, albumin, gelatin, hyaluronic acid, starch, celluloses
such as methyl cellulose hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, carboxymethylcellulose phthalate;
casein, dextrans, polysaccharides, fibrinogen, poly(D,L-lactide),
poly(D,L-lactide-co-glycolide), poly(glycolide),
poly(hydroxybutylate), poly(alkyl carbonate), poly(orthoester),
polyester, poly(hydroxyvaleric acid), polydioxanone, poly(ethylene
terephtalate), poly(malic acid), poly(tartronic acid),
polyanhydrides, polyphosphazenes, poly(amino acids) and their
copolymers.
19. The method according to claim 1 wherein the functionalization
includes applying non-biodegradable and/or non-absorbable polymers
such as poly(ethylene vinyl acetate), silicones, acrylic polymers
such as polyacrylic acid, polymethyl acrylic acid, polyacryl
cyanoacrylate; polyethylenes, polypropylenes, polyamides,
polyurethanes, poly(ester urethanes), poly(ether urethanes),
poly(ester ureas), polyethers, polyethylene oxide, polypropylene
oxide, pluronics, polytetramethylene glycol; vinyl polymers such as
polyvinylpyrrolidones, poly(vinyl alcohols), poly(vinyl acetate
phthalate) as well as their copolymers.
20. An implant having a functionalized surface produced according
to the method of claim 1.
21. The implant according to claim 20 wherein the implant is made
of metals such as stainless steel, titanium, tantalum, platinum,
gold, palladium, alloys, in particular memory alloys such as
nitinol or nickel titanium alloys or carbon fibers, solid carbon
material or carbon composites.
22. The implant according to claim 20 further comprising multiple
carbon-based layers optionally loaded with active ingredient.
23. A device according to claim 20 further comprising anionic or
cationic or amphoteric coatings selected from alginate,
carrageenan, carboxymethyl cellulose, poly(meth)acrylates,
chitosan, poly-L-lysines and/or phosphorylcholine.
24. A stent coated with an active ingredient according to claim
20.
25. A heart valve coated with an active ingredient according to
claim 20.
26. The implant according to claim 20 in the form of an orthopedic
bone prosthesis or joint prosthesis, a bone substitute or a
vertebral substitute in the thoracic or lumbar region of the spinal
column.
27. An active ingredient depot with controlled release that can be
used subcutaneously and/or intramuscularly having a functionalized
surface produced according to the method of claim 1.
28. The implant according to claim 20 further comprising applied
and/or incorporated microorganisms, viral vectors or cells or
tissue.
29. A use of an implant of claim 28 for producing a therapeutic
effect or for increasing the bioavailability of the implant after
implantation of the implant in the human body.
Description
INCORPORATION BY REFERENCE
[0001] This application is a continuation-in-part application of
international patent application Serial No. PCT/EP2004/005785 filed
May 28, 2004, which claims benefit of German patent application
Serial Nos. DE 103 24 415.8 filed May 28, 2003; DE 103 33 098.4
filed Jul. 21, 2003 and DE 103 33 099.2 filed Jul. 21, 2003.
[0002] The foregoing applications, and all documents cited therein
or during their prosecution ("appln cited documents") and all
documents cited or referenced in the appln cited documents, and all
documents cited or referenced herein ("herein cited documents"),
and all documents cited or referenced in herein cited documents,
together with any manufacturer's instructions, descriptions,
product specifications, and product sheets for any products
mentioned herein or in any document incorporated by reference
herein, are hereby incorporated herein by reference, and may be
employed in the practice of the invention.
FIELD OF THE INVENTION
[0003] The present invention relates to a method for producing
medical implants having functionalized surfaces by providing a
medical implant with at least one carbon-based layer on at least a
portion of the surface of the implant, activating the carbon-based
layer by creating porosity and functionalizing the activated
carbon-based layer; this invention also relates to functionalized
implants obtainable by this method.
BACKGROUND OF THE INVENTION
[0004] Medical implants such as surgical and/or orthopedic screws,
plates, joint prostheses, artificial heart valves, vascular
prostheses, stents as well as subcutaneously or intramuscularly
implantable active agent depots are produced from a wide variety of
materials, which are selected according to specific biochemical and
mechanical properties. These materials must have certain mechanical
and biochemical properties, must not release any toxic substances
and must be suitable for long-term use in the body.
[0005] However, the metals or metal alloys and ceramic materials
frequently used for stents and joint prostheses, for example, often
have disadvantages with regard to their biocompatibility or
functionality, in particular in long-term use. Implants trigger
inflammatory tissue responses and immune reactions through chemical
and/or physical irritation, thus resulting in intolerance reactions
in the sense of chronic inflammatory reactions with defensive and
rejection reactions, excessive scar tissue production or
degradation of tissue, which in the extreme case must result in the
implant having to be removed and replaced or additional therapeutic
interventions of an invasive or noninvasive type being
indicated.
[0006] For this reason, there are various approaches in the state
of the art for coating surfaces of medical implants in a suitable
way to increase the biocompatibility of the materials used or the
functional efficacy of the implants and to prevent defensive
reactions, i.e., rejection.
[0007] U.S. Pat. No. 5,891,507, for example, discloses methods for
coating the surface of metal stents with silicone,
polytetrafluoroethylene and biological materials such as heparin or
growth factors which increase the biocompatibility of the metal
stents.
[0008] In addition to plastic layers, carbon-based layers have
proven to be particularly advantageous.
[0009] For example, German Patent DE 199 51 477 describes coronary
stents with a coating of amorphous silicon carbide, which increases
the biocompatibility of the stent material. U.S. Pat. No. 6,569,107
describes carbon-coated stents in which the carbon material is
applied by chemical or physical vapor-phase deposition methods (CVD
or PVD). U.S. Pat. No. 5,163,958 also describes tubular
endoprostheses or stents with a coated surface having
antithrombogenic properties. WO 02/09791 describes intravascular
stents with coatings produced by CVD of siloxanes.
[0010] In addition to the CVD methods for deposition of carbon,
various high-vacuum sputtering methods have been described in the
state of the art for production of pyrolytic carbon layers with
various structures (see U.S. Pat. No. 6,355,350, for example).
[0011] The implants with modified surfaces produced in this way
still have some disadvantages, however. The biocompatibility is not
adequate in all cases to completely prevent rejection reactions.
Furthermore, the surface-coated implants of the state of the art
usually have closed pores, which make intergrowth with the
surrounding body tissue difficult or impossible and/or restrict
functionalization. Although the prior art implants can also be
coated with antibiotics, the effect of the substances after
implanting the implant is always short lasting, however, because
the quantities of active ingredient applied are limited by the
nature of the implant and by its surface coating or its desorption
cannot be controlled or its efficacy is impaired by physical or
chemical interactions with the coating.
[0012] Furthermore, it is appropriate and advisable from a medical
standpoint if implants can be used not only in their supporting
function, as is the case with stents, but can also be provided with
additional functions, e.g., long-term delivery of medications at
the site of implantation of the implant to potentiate the effect of
the implant or to achieve additional medically desirable
effects.
[0013] There has therefore been a demand for inexpensive,
easy-to-use methods for producing functionalized implants.
[0014] Furthermore, there has also been a demand for medical
implants that are inexpensive to manufacture and have improved
properties.
[0015] Citation or identification of any document in this
application is not an admission that such document is available as
prior art to the present invention.
SUMMARY OF THE INVENTION
[0016] One object of the present invention is therefore to make
available a method for producing implants with an additional
functionality.
[0017] Another object of the present invention is to make available
medical implants which can assume additional functions, such as the
release of pharmaceutical substances in the body or the growth of
tissue, and thereby have increased biocompatibility and/or have a
stronger functional implant effect.
[0018] Another object of the present invention is to make available
medical implants which permit a long-term release of medical active
ingredients in the body of the patient or which have a function
that is improved by surface modification.
[0019] Yet another function of the present invention is make
available medical implants which can release pharmacologically
active substances that are applied to or incorporated into the
implant in a controlled manner after implantation of the implant in
the human body.
[0020] Another object of this invention is to provide implantable
active ingredient depots with a coating which is capable of
controlling the release of active ingredients from the depot.
[0021] Another object of this invention is to make available
medical implants which contain applied and/or incorporated
microorganisms, viral vectors or cells or tissue, so that after the
implant has been implanted in the human body, a therapeutic effect
can be achieved in a control manner or the bioavailability can be
increased.
[0022] The inventive solution to the objects indicated above
consists of a method and medical implants obtainable by this method
as defined in the independent claims. Preferred embodiments of the
inventive method and/or the inventive products and uses are derived
from the dependent subordinate claims.
[0023] Within the context of the present invention, it has been
discovered that carbon-based layers in particular on implantable
medical devices of a wide variety of types can be utilized easily
to equip the implant with additional medical physiological and
therapeutic functions.
[0024] It is possible in particular according to this invention to
apply therapeutically active quantities of pharmaceutical agents to
the surface of an implant or in a layer present on the implant and
to release these substances continuously in a controlled manner in
the human body.
[0025] Accordingly, the inventive method for producing medical
implants having functionalized surfaces comprises the following
steps:
[0026] a) providing a medical implant with at least one
carbon-based layer on at least a portion of the surface of the
implant;
[0027] b) activating the carbon-based layer by creating
porosity;
[0028] c) functionalizing the activated carbon-based layer.
[0029] With the inventive method, it is possible to suitably modify
implants having carbon-based surface coatings to make it possible
to load them with therapeutically active amounts of active
pharmacologic substances. By creating porosity in carbon-based
surface layers of a suitable thickness, controlled
adjustment/modification of the pore size and/or pore structure and
optionally a suitable surface coating that modifies release, it is
possible to adjust and vary in a controlled manner the load
quantity, type and rate of release as well as the biological
physiological surface properties. This also makes it possible to
implement embodiments tailored to each specific type of implant and
active ingredient as well as each site of application and intended
use of medical implants with simple procedural measures such as
those described according to this invention.
[0030] It is noted that in this disclosure and particularly in the
claims and/or paragraphs, terms such as "comprises", "comprised",
"comprising" and the like can have the meaning attributed to it in
U.S. Patent law; e.g., they can mean "includes", "included",
"including", and the like; and that terms such as "consisting
essentially of" and "consists essentially of" have the meaning
ascribed to them in U.S. Patent law, e.g., they allow for elements
not explicitly recited, but exclude elements that are found in the
prior art or that affect a basic or novel characteristic of the
invention.
[0031] These and other embodiments are disclosed or are obvious
from and encompassed by, the following Detailed Description.
DETAILED DESCRIPTION
[0032] Implants coated with a carbon-based coating can be
functionalized by the method according to this invention.
[0033] The terms "implantable medical device" and "implant" are
used synonymously here and are understood to include medical or
therapeutic implants, such as vascular endoprostheses, intraluminal
endoprostheses, stents, coronary stents, peripheral stents,
surgical and/or orthopedic implants for temporary use, such as
surgical screws, plates, nails and other fastening means, permanent
surgical or orthopedic implants, such as bone prostheses or joint
prostheses, e.g., artificial hip or knee joints, socket joint
inserts, screws, plates, nails, implantable orthopedic fixation
aids, vertebral prostheses and artificial hearts and parts thereof
as well as artificial heart valves, heart pacemaker casings,
electrodes, subcutaneous and/or intramuscularly implantable
implants, active ingredient depots and microchips and the like.
[0034] The implants that can be used in the inventive method may
consist of almost any materials, preferably those that essentially
have thermal stability, in particular all materials of which such
implants are typically produced.
[0035] Examples include, but are not limited to, amorphous and/or
(partially) crystalline carbon, solid carbon material, porous
carbon, graphite, carbon composite materials, carbon fibers,
ceramics such as zeolites, silicates, aluminum oxides,
aluminosilicates, silicon carbide, silicon nitride, metal carbides,
metal oxides, metal nitrides, metal carbonitrides, metal
oxycarbides, metal oxynitrides and metal oxycarbonitrides of the
transition metals, such as titanium, zirconium, hafnium, vanadium,
niobium, tantalum, chromium, molybdenum, tungsten, manganese,
rhenium, iron, cobalt, nickel; metals and metal alloys, in
particular the noble metals such as gold, silver, ruthenium,
rhodium, palladium, osmium, iridium, platinum; metals and metal
alloys of titanium, zirconium, hafnium, vanadium, niobium,
tantalum, chromium, molybdenum, tungsten, manganese, rhenium, iron,
cobalt, nickel, copper; steel, in particular stainless steel,
memory alloys such as nitinol, nickel titanium alloy, glass, stone,
glass fibers, minerals, natural or synthetic bone substance,
imitation bone based on alkaline earth metal carbonates such as
calcium carbonate, magnesium carbonate, strontium carbonate, foamed
materials such as polymer foams, foamed ceramics and the like as
well as any combinations of the aforementioned materials.
[0036] In preferred embodiments of the present invention, the
implants used are stents, in particular metal stents, preferably
made of stainless steel, platinum-based radiopaque steel alloys,
so-called PERSS (platinum-enhanced radiopaque stainless steel
alloys), cobalt alloys, titanium alloys, high-melting alloys, e.g.,
based on niobium, tantalum, tungsten and molybdenum, noble metal
alloys, nitinol alloys as well as magnesium alloys and mixtures of
the above.
[0037] Especially preferred implants within the scope of the
present invention include, but are not limited to, stents made of
stainless steel, in particular Fe-18Cr-14Ni-2.5Mo ("316LVM" ASTM F
138), Fe-21Cr-10Ni-3.5Mn-2.5Mo (ASTM F 1586), Fe-22Cr-13Ni-5Mn
(ASTM F 1314), Fe-23Mn-21Cr-1Mo-1N (nickel-free stainless steel);
stents made of cobalt alloys such as Co-20Cr-15W-10Ni ("L605" ASTM
F 90), Co-20Cr-35Ni-10Mo ("MP35N" ASTM F 562),
Co-20Cr-16Ni-16Fe-7Mo ("Phynox" ASTM F 1058). Examples of preferred
titanium alloys include, but are not limited to, CP titanium (ASTM
F 67, Grade 1), Ti-6Al-4V (alpha/beta ASTM F 136), Ti-6Al-7Nb
(alpha/beta ASTM F1295), Ti-15Mo (beta grade ASTM F 2066); stents
made of noble metal alloys in particular alloys containing iridium
such as Pt-10Ir; nitinol alloys such as martensitic, superelastic
and cold-workable (preferably 40%) nitinols and magnesium alloys
such as Mg-3Al-1Z.
[0038] The implantable medical devices that can be used according
to this invention may have almost any external form. The inventive
method is not limited to certain structures.
[0039] The implants must have a carbon-based layer on at least a
portion of their surface. This layer may consist of pyrolytically
produced carbon, vitreous amorphous carbon, vapor-deposited carbon,
carbon applied by CVD, PVD or sputtering, diamond-like, graphitic
carbon, metal carbides, metal carbonitrides, metal oxynitrides or
metal oxycarbides as well as any combinations thereof. The
carbon-based layer may be amorphous, partially crystalline or
crystalline, preferably consisting of layers of amorphous pyrolytic
carbon, and in some embodiments it may also be diamond-like, e.g.,
vapor-deposited carbon.
[0040] Implants with a carbon-based coating produced by applying
material that produce carbon and/or polymer films to the implant
and then carbonizing these materials in the absence of oxygen at
elevated temperatures are especially preferred. Examples are
disclosed in German Patent DE 10322187 and/or PCT/EP2004/005277,
German Patent DE 10324415 and/or PCT/EP2004/004987 and German
Patent DE 10333098 and/or PCT/EP2004/004985, the disclosures of
which are herewith fully incorporated by reference.
[0041] Other suitable implants with a carbon-based coating include,
but are not limited to, commercial carbon-coated implants such as
metal stents of the Radix Carbostent.RTM. type (Sorin Biomedica)
and the like, most of which have carbon coatings produced by
physical vapor deposition or atomization methods, including
sputtering.
[0042] The thickness of one or more carbon-based layers may in
general be from 1 nm to 1 mm, optionally even several millimeters,
e.g., up to 10 mm, preferably up to 6 mm, especially preferably up
to 2 mm, in particular between 10 nm and 200 .mu.m.
[0043] In preferred embodiments of the present invention, the
implantable medical devices may also have multiple carbon-based
layers of the same or different thickness and/or porosity. For
example, it is possible to combine deeper more porous layers with
narrow-pored layers above them which can suitably delay the release
of the active ingredients deposited in the more porous layer.
[0044] According to the inventive method, the physical and chemical
properties of the carbon-based coating are further modified by
suitable activation steps and adapted to the intended purpose.
Traditional carbon-based implants usually have essentially closed
surfaces, which greatly restrict effective and long-lasting loading
with active ingredients, for example, or limit it to a very small
amount. The purpose of activation is to create porosity in the
carbon-based layer and/or to form a porous carbon-based layer on
the implant in order to thereby permit better functionalization by
means of active ingredients, cells, proteins, microorganisms, etc.,
and to increase the ability to uptake the carbon-based layer per
unit of area.
[0045] The activation step in the inventive method thus consists
essentially of creating porosity in the carbon layer on the
implant. Several possibilities are available here.
[0046] One possible method of activating the carbon layer includes,
but is not limited to, for example, reductive or oxidative
treatment steps in which the layer is treated one or more times
with suitable reducing agents and/or oxidizing agents, such as
hydrogen, carbon dioxide, water vapor, oxygen, air, nitrous oxide
or oxidizing acids such as nitric acid and the like and optionally
mixtures of these.
[0047] Activation with air is preferred, especially preferably at
an elevated temperature.
[0048] The activation step(s) may be carried out at an elevated
temperature, e.g., from 40.degree. C. to 1000.degree. C.,
preferably 70.degree. C. to 900.degree. C., especially preferably
from 100.degree. C. to 850.degree. C., in particular preferably
from 200.degree. C. to 800.degree. C. and most especially at
approximately 700.degree. C. In especially preferred embodiments,
the carbon-based layer is modified by reduction or oxidation or a
combination of these treatment steps at room temperature. Boiling
in oxidizing acids or bases may also be used to produce a porous
surface.
[0049] The pore size and pore structure can be varied according to
the type of oxidizing agent or reducing agent used, the temperature
and the duration of the activation. In particularly preferred
embodiments, carbon-based medical implants activated according to
this invention can be used for controlled release of active
ingredients from the substrate into the environment through
targeted adjustment of the porosity of the carbon layer.
[0050] The coatings are preferably porous after activation, in
particular having a nanoporosity. Medical implants can be used as a
drug vehicle with a depot effect according to this invention, for
example, in particular when the implant itself also has a porous
structure, in which the activated carbon-based layer of the implant
can be used as a membrane which regulates the rate of release.
[0051] In preferred embodiments, the porosity can be adjusted by
washing out fillers that are present in the carbon-based coating,
e.g., polyvinylpyrrolidone, polyethylene glycol, powdered aluminum,
fatty acids, microwaxes or emulsions, paraffins, carbonates,
dissolved gases or water-soluble salts with water, solvents, acids
or bases or by distillation or oxidative and/or non-oxidative
thermal decomposition. Suitable methods of this are described in
German Patent DE 103 22 187 and/or PCT/EP2004/005277, for example,
by the present applicant, the disclosures of which are herewith
fully incorporated by reference.
[0052] The porosity may optionally also be created by structuring
the surface with powdered substances such as metal powder, carbon
black, phenolic resin powder, fibers, in particular carbon fibers
or natural fibers.
[0053] Another possibility for activation and/or producing porosity
is by sputtering the carbon-based layer with suitable elements or
so-called ion bombardment, e.g., with noble gas ions or the
like.
[0054] The activated coating may optionally also be subjected to a
so-called CVD process (chemical vapor deposition) or CVI process
(chemical vapor infiltration) in another optional process step in
order to further modify the surface structure or pore structure and
its properties. To do so, the carbonized coating is treated with
suitable precursor gases that release carbon at high temperatures.
Subsequent application of diamond-like carbon is preferred here.
Other elements may also be deposited in this way, such as silicon.
Such methods are known in the state of the art.
[0055] Almost all known saturated and unsaturated hydrocarbons with
sufficient volatility under CVD conditions may be used as the
precursors to split off carbon. Examples include, but are not
limited to, methane, ethane, ethylene, acetylene, linear and
branched alkanes, alkenes and alkynes with carbon numbers of
C.sub.1 to C.sub.20, aromatic hydrocarbons such as benzene,
naphthalene, etc., and aromatics with one or more alkyl, alkenyl
and alkynyl substituents, such as toluene, xylene, cresol, styrene,
etc.
[0056] Suitable ceramic precursors include, but are not limited to,
for example, BCl.sub.3, NH.sub.3, silanes such as SiH.sub.4,
tetraethoxysilane (TEOS), dichlorodimethylsilane (DDS),
methyltrichlorosilane (MTS), trichlorosilyldichloroborane (TDADB),
hexadichloromethylsilyloxide (HDMSO), AlCl.sub.3, TiCl.sub.3 or
mixtures thereof.
[0057] In the CVD method, the precursors are mostly used in a low
concentration of approximately 0.5 to 15 vol % in mixture with an
inert gas such as nitrogen, argon or the like. Hydrogen may also be
added to the corresponding gas mixtures for deposition. At
temperatures between 500.degree. C. and 2000.degree. C., preferably
500.degree. C. to 1500.degree. C. and especially preferably
700.degree. C. to 1300.degree. C., the compounds mentioned above
split off hydrocarbon fragments and/or carbon or ceramic
precursors, which are deposited in an essentially uniform
distribution in the pore system of the pyrolyzed coating, where
they modify the pore structure and produce an essentially
homogeneous pore size and pore distribution.
[0058] By means of CVD methods, the size of pores in the
carbon-based layer on the implant can be reduced in a controlled
manner or the pores may even be completely closed and/or sealed.
This makes it possible to adjust the sorptive properties as well as
the mechanical properties of the activated implant surface in a
tailored manner.
[0059] By CVD of silanes or siloxanes, optionally in mixture with
hydrocarbons, the carbon-based implant coatings can be modified by
formation of carbide or oxycarbide, so that they are resistant to
oxidation, for example.
[0060] In preferred embodiments, the coated implants activated
according to this invention can be additionally coated and/or
modified by sputtering methods. Carbon, silicon and metals and/or
metal compounds can be applied by essentially known methods from
suitable sputter targets. For example, by incorporating silicon
compounds, titanium compounds, zirconium compounds, or tantalum
compounds or metals by CVD or PVD into the carbon-based layer, it
is possible to form carbide phases which increase the stability and
oxidation resistance of the layer.
[0061] In another preferably embodiment of the activation step,
carbon-based layers, even sputtered carbon layers, for example, can
be worked mechanically afterwards to produce porous surfaces. For
example, controlled abrasion of these layers by suitable methods
leads to porous layers. A preferred option is abrasion of such
carbon-based layers in an ultrasonic bath, where defects in the
layers and thus porosity can be produced in a targeted manner by
admixture of abrasive solids of various particle sizes and degrees
of hardness by appropriate input of energy and a suitable frequency
of the ultrasonic bath as a function of treatment time.
[0062] Aqueous ultrasonic baths to which alumina, silicates,
aluminates and the like have been added, preferably alumina
dispersions, are preferred here. However, any other solvents that
are suitable for ultrasonic baths may also be used instead of or in
combination with water.
[0063] For example, by treatment of carbon-coated implants in an
aqueous ultrasonic bath with the admixture of alumina, preferably
1% to 60% alumina dispersions, it is possible to produce
nano-abraded carbon layers with an average pore size of
approximately 5 nm to 200 nm.
[0064] Furthermore, by ion implantation of metals, in particular
transition metals and/or non-metals, the surface properties of the
implant can be further modified. For example, by nitrogen
implantation it is possible to incorporate nitrides, oxynitrides or
carbonitrides, in particular those of the transition metals. The
porosity and strength of the surface materials can be further
modified by implantation of carbon.
[0065] The carbon-based layer is preferably porous after
activation, with pore diameters in the range of 0.1 .mu.m to 1000
.mu.m, preferably between 1 .mu.m and 400 .mu.m. Macroporous layers
can also be produced with the inventive activation steps.
[0066] The carbon-based layer is especially preferably nanoporous
after activation with pore diameters of 1 nm to 1000 nm, preferably
from 5 nm to 900 nm.
[0067] In an especially preferred embodiment of this invention, the
activation is performed during the step of production of the
carbon-based layer, e.g., by applying one or more porous
carbon-based layers, by carbonization of substances that produce
carbon, by coating with carbon by CVD or PVD and/or by applying
suitable layers of porous biodegradable and/or resorbable or
non-biodegradable and/or resorbable polymers.
[0068] It is especially preferable for one or more porous
carbon-based layers to be applied by coating the implant with an
optionally foamed polymer film or one containing fillers and then
carbonizing the polymer film at temperature of 200.degree. C. to
3500.degree. C., preferably up to 2000.degree. C. in an oxygen-free
atmosphere, optionally partially oxidized in an air stream
subsequently. Corresponding methods are described, for example, in
German Patent DE 10324415 and/or PCT/EP2004/004987 and in German
Patent DE 10333098 and/or PCT/EP2004/004985, the disclosures of
which are herewith fully incorporated by reference.
[0069] Thus, for example, adding polyethylene glycol to the polymer
film that is to be carbonized produces defects in the polymer
crosslinking which in turn produce a porous carbon layer after
thermal treatment or dissolving in suitable solvents. Porosity
suitable for a given application can be achieved through the choice
of the polymer system, the molecular weight of polyethylene glycol
and the polyethylene glycol solids content, and in particular the
average porosity, the pore size distribution and the degree of
porosity can be adjusted. For example, by selecting polyethylene
glycols with a molecular weight of 1000 to 8,000,000 Dalton, it is
possible to produce pore sizes from 10 nm to 1000 nm or in a
preferred embodiment from 50 nm to 1000 nm. By varying the solids
content from 10% to 80%, a degree of porosity from 5% to 80% can be
produced, preferably 20% to 60%.
[0070] Another example of this type of combined production and
activation of the carbon-based layer is by admixture of carbon
black to the polymer film. Through the choice of the average
particle size and the solids content in the polymer film, it is
possible to produce porous matrices in which the degree of porosity
and average pore size can be adjusted through the choice of
suitable polymer systems, carbon black particle sizes and the
solids content, depending on the application. Thus, for example, by
admixture of carbon black particles with an average particle size
of 10 nm to 1 mm, preferably 10 nm to 1000 nm, with a solids
content of 20% to 80%, preferably 30% to 60%, an average porosity
of 30% to 60% can be produced, with the pore sizes produced being
adjustable between 10 nm and 1000 nm, preferably from 10 nm to 800
nm.
[0071] Furthermore, by optional parylenation of the implants before
or after the activation steps, the surface properties and porosity
of the carbon-based layer can be further modified. The implants
here are first treated with paracyclophane at an elevated
temperature, usually approximately 600.degree. C., with a polymer
film of poly(p-xylylene) being formed on the surface of the
implants. This film can then be converted to carbon by known
methods in a subsequent carbonization step.
[0072] If necessary, in particularly preferred embodiments, the
activated implant may be subjected to additional chemical and/or
physical surface modifications. Cleaning steps to remove any
residues and impurities that might be present may also be provided
here. For this purpose, acids, in particular oxidizing acids, or
solvents may be used, but boiling in acids or solvents is
preferred. Carboxylation of these activated carbon layers can be
achieved by boiling in oxidizing acids.
[0073] Before medical use or loading with active ingredients, the
inventive implants may be sterilized by conventional methods, e.g.,
by autoclaving, ethylene oxide sterilization or
gamma-radiation.
[0074] According to this invention, all possible activation methods
may be combined or used with any of the functionalization steps
described below.
[0075] The implants may be additionally equipped with a number of
functions by suitable measures. Orthopedic and surgical implants or
vascular endoprostheses may be used as drug vehicles or depots. The
biocompatibility and functionality of the inventive implants can be
influenced or altered in a controlled manner by incorporating
additives, fillers, proteins, etc. This makes it possible to reduce
or entirely prevent rejection reactions in the body when using
implants produced according to this invention or the efficacy of
the implant may be increased and/or additional effects
achieved.
[0076] Functionalization in the sense of the present invention is
understood to refer in general to measures as a consequence of
which the carbon-based layer gains additional functions.
Functionalization according to this invention consists of
incorporating substances into the carbon-based layer or attaching
substances to the carbon-based layer. Suitable substances are
selected from pharmacological active ingredients, linkers,
microorganisms, cells of plant or animal origin including human
cells or cell cultures and tissue, minerals, salts, metals,
synthetic or natural polymers, proteins, peptides, amino acids,
solvents, etc.
[0077] According to this invention, the suitably activated implant
can be functionalized by making it more biocompatible before or
after a possible loading with active ingredients. This is done by
coating it with at least one additional layer of biodegradable
and/or absorbable polymers such as collagen, albumin, gelatin,
hyaluronic acid, starch, celluloses such as methyl cellulose
hydroxypropylmethyl cellulose, carboxymethyl cellulose phthalate;
casein, dextrans, polysaccharides, fibrinogen, poly(D,L-lactides),
poly(D,L-lactide-co-glycolides), poly(glycolides),
poly(hydroxybutylates), poly(alkyl carbonates), poly(orthoesters),
polyesters, poly(hydroxyvaleric acid), polydioxanones,
poly(ethylene terephtalate), poly(malic acid), poly(tartronic
acid), polyanhydrides, polyphosphazenes, poly(amino acids) and
their copolymers or non-biodegradable and/or absorbable polymers.
In particular anionic, cationic or amphoteric coatings are
especially preferred, such as alginate, carrageenan, carboxymethyl
cellulose, chitosan, poly-L-lysine and/or phosphorylcholine.
[0078] In the functionalization step of the inventive method,
active ingredients such as pharmaceutical drugs and medications may
be applied to the activated carbon-based layer or incorporated into
the layer. This is useful in particular in cases where active
ingredients cannot be applied in or to the implant directly as in
the case of metals, for example.
[0079] For example, sparingly water-soluble lipophilic active
ingredients such as paclitaxel are difficult to apply to metallic
surfaces because they tend to form a crystalline film. Usually the
immobilizable quantities are limited and the release cannot be
controlled. Direct coating of such metallic surfaces with
paclitaxel leads to maximum loading of approximately 3 mg/mm.sup.2,
the release of which under physiological conditions in
physiological buffer solutions leads to uncontrolled desorption of
max. 30% with in one to five days.
[0080] Carbon layers activated according to this invention,
preferably vitreous amorphous carbon with a layer thickness in the
range of 80 nm to 10 .mu.m, preferably 100 nm to 5 .mu.m,
preferably with a pore size of 5 nm to 100 .mu.m, preferably from 5
nm to 1000 nm can take up active ingredient quantities amounting to
up to 100 times that of non-activated carbon-coated or purely
metallic implants e.g., even at porosities of 5 to 50%, preferably
10 to 50% and an average pore size of 5 nm to 1 .mu.m, preferably
from 5 nm to 500 nm, and can optionally release these active
ingredients in a controlled manner as a function of the porosity
and/or pore size and/or surface properties.
[0081] In an inventive embodiment with a pore size of 50 nm and a
porosity of 5%, for example, and with a load of 0.5 to 3.0
.mu.mm.sup.2 paclitaxel and hydrophobic carbon surfaces with a
layer thickness of 200 nm, 70% to 100% of the applied dosage of
paclitaxel can be released in a controlled manner at a constant
daily release rate under physiological conditions within 25 to 35
days.
[0082] In particularly preferred embodiments, through suitable
functionalization of any carbon-based layer, peptides and proteins
as well as glycoproteins and lipoproteins can also be
immobilized.
[0083] An inventive form of functionalization consists of covalent
or non-covalent adsorption of substances which allow the binding of
peptides, proteins, glycoproteins or lipoproteins labeled or
otherwise provided with affinity tags.
[0084] Such substances include, but are not limited to, for
example, ions, cations, in particular metal cations such as cobalt,
nickel, copper and zinc cations, antibodies, calmodulin, chitin,
cellulose, sugars, amino acids, glutathione, streptavidin,
Strep-Tactin or other mutants for binding Strep-tag- or
SBP-tag-labeled substances or S protein for binding S-tag-labeled
substances, etc.
[0085] These affinity tags are attached by a suitable method to the
peptides, proteins, glycoproteins or lipoproteins to be
immobilized, attaching the either the C terminus or N terminus of
the primary sequence, usually by the methods of recombinant genetic
engineering or biotinylation. Affinity tags, in particular
polyarginine tags (Arg tag) are preferred, the latter preferably
consisting of five to six argininic acids, polyhistidine tags (His
tags), a polyhistidine sequence of any desired length, typically
two to ten radicals, FLAG tags with the sequence DYKDDDDK, Strep
tags, e.g., the Strep tag II sequence WSHPQFEK, S tags which carry
the amino acid radicals KETAAAKFERQHMDS, calmodulin-binding
peptide, the family of cellulose-binding domains, in particular
C-terminal, N-terminal or other positions in the primary sequence
of the peptide, protein, glycoprotein or lipoprotein to be
immobilized, the SBP tag with the sequence
MDEKTTGWRGGHVVEGLAGELEQLRARLEH- HPQGQREP, the polyhistidine tag,
chitin-binding domains, glutathione S-transferase tag,
maltose-binding protein, bacteriophage T7 and V5 epitope, but also
any other type of affinity tag.
[0086] The modification of the substances to be applied to the
functionalized carbon surfaces corresponds to the usual methods
that are possible in purification and in particular chromatographic
labeling.
[0087] Functionalization of the carbon surface is accomplished here
by adsorption of corresponding substances in and/or on the
carbon-based layer such that these substances can enter into a bond
with the affinity tags. Corresponding substances include, but are
not limited to, for example, cations which are introduced into the
carbon layer to permit binding to the basic polyarginine tag, e.g.,
cobalt, nickel, copper and zinc cations to permit binding of
polyhistidine tags, for example.
[0088] Adsorption of the antibody M1 on the carbon surfaces permits
the binding of FLAG tags, streptavidin or Strep-Tactin or SBP
tag-labeled substances or adsorption of the S protein on the
surface to bind S tag labeled substances.
[0089] In another embodiment, the functionalization consists of
using calmodulin which is to be adsorbed on the carbon surface.
This makes it possible to bind calmodulin-binding peptide-labeled
substances to the carbon-based layer.
[0090] In other embodiments, the functionalization is accomplished
by adsorption of cellulose, so that substance modified with
cellulose binding domains can be bound or it is accomplished by
adsorption of chitin to bind substances provided with
chitin-binding domains.
[0091] Similarly, functionalization may be performed with
glutathione for binding glutathione S-transferase tag-labeled
substances, or with maltose or amylose to bind maltose binding
protein labeled substances.
[0092] Those skilled in the art will select a suitable affinity
system in accordance with the conditions that are possible in
genetic engineering, the functional and structural properties of
the peptide, protein, glycoprotein or lipoprotein.
[0093] For example, carbon layers functionalized with 0.1-8
.mu.g/mm.sup.2 adsorbed Strep-Tactin can be obtained from a
Strep-Tactin solution on porous carbon surfaces with a pore size of
100 to 900 nm, a porosity of 30% to 60% and a layer thickness of 1
to 5 .mu.m by spraying or dipping carbon layers. The carbon layer
functionalized in this way can take up, for example, 0.1 to 10
.mu.g/mm.sup.2 Strep-tag-labeled recombinant IL-2.
[0094] In another embodiment, the carbon layer is doped with cobalt
ions, where the porous carbon matrix has a cobalt ion content of
0.1 to 50% of the solids content, preferably up to 60% in vitreous
porous carbon layers. At a porosity of 50%, layer thickness of 500
nm to 1000 nm, 0.1 to 100 .mu.g polyarginine tag-labeled
recombinant IL-2 can be adsorbed by the metal ion doping in the
matrix.
[0095] Another embodiment involves, for example, functionalization
of the carbon surfaces by adsorption of linker substances,
preferably carboxymethylated dextrans, e.g., as a hydrogel, which
permits physical binding of substances, preferably biomolecules or
active ingredients and/or have a chemical reactivity so that such
substances can be attached by covalent bonds, preferably by forming
amino, thiol or aldehyde bonds.
[0096] Those skilled in the art will select a suitable type of
linker as a function of the type of ligand.
[0097] For the production of an amino bond, the carbon layer can be
functionalized as follows in a preferred embodiments: adsorption of
carboxymethylated dextran, subsequent modification by modification
in NHS/EDC to convert the carboxymethyl groups into
hydroxysuccinimide esters.
[0098] This makes it possible to adsorb ligands which enter into
covalent amino bonds with the esters. Unreacted esters can be
inactivated again in another step, e.g., by incubation in 1M
ethanolamine hydrochloride solution. For example, adsorption of 1
.mu.g carboxymethylated dextran per mm.sup.2 of a porous
carbon-based composite layer of vitreous carbon and carbon black
particles yields a functionalization which can bind 0.01 to 5000
.mu.g/mm.sup.2 peptides with a molecular weight of 60 to 90 by
covalent bonding.
[0099] Furthermore, the porous layers activated according to this
invention can be loaded with pharmaceutical drugs, i.e.,
medications, microorganisms, cells and/or tissues in the
functionalization step of the process or they may be provided with
diagnostic aids such as markers or contract media for localizing
coated implants in the body, e.g., even with therapeutic or
diagnostic quantities of radioactive substances.
[0100] In preferred embodiments, the implants activated according
to this invention are loaded with active ingredients in the
functionalization step. Active ingredients may be loaded into or
onto the carbon-based layer by suitable sorptive methods such as
adsorption, absorption, physisorption or chemisorption; in the
simplest case, they may be loaded by impregnation of the
carbon-based coating with active ingredient solutions, active
ingredient dispersions or active ingredient suspensions in suitable
solvents. Covalent or non-covalent bonding of active ingredients in
or on the carbon-based coating here may be a preferred option,
depending on the active ingredient used and its chemical
properties.
[0101] In preferred embodiments, the active ingredient is applied
in the form of a solution, dispersion or suspension in a suitable
solvent or solvent mixture, optionally with subsequent drying.
Suitable solvents include, but are not limited to, for example
methanol, ethanol, n-propanol, isopropanol, butoxydiglycol,
butoxyethanol, butoxyisopropanol, butoxypropanol, n-butyl alcohol,
t-butyl alcohol, butylene glycol, butyloctanol, diethylene glycol,
dimethoxydiglycol, dimethyl ether, dipropylene glycol,
ethoxydiglycol, ethoxyethanol, ethylhexanediol, glycol, hexanediol,
1,2,6-hexanetriol, hexyl alcohol, hexylene glycol,
isobutoxypropanol, isopentyldiol, 3-methoxybutanol,
methoxydiglycol, methoxyethanol, methoxyisopropanol,
methoxymethylbutanol, methoxy PEG-10, methylal, methyl hexyl ether,
methylpropanediol, neopentyl glycol, PEG-4, PEG-6, PEG-7, PEG-8,
PEG-9, PEG-6-methyl ether, pentylene glycol, PPG-7, PPG-2-buteth-3,
PPG-2 butyl ether, PPG-3 butyl ether, PPG-2 methyl ether, PPG-3
methyl ether, PPG-2 propyl ether, propanediol, propylene glycol,
propylene glycol butyl ether, propylene glycol propyl ether,
tetrahydrofuran, trimethylhexanol, phenol, benzene, toluene,
xylene; as well as water, optionally in mixture with dispersion
aids and also mixtures of the aforementioned substances.
[0102] Preferred solvents include, but are not limited to, one or
more organic solvents from the group consisting of ethanol,
isopropanol, n-propanol, dipropylene glycol methyl ether and
butoxyisopropanol (1,2-propylene glycol n-butyl ether),
tetrahydrofuran, phenol, benzene, toluene, xylene, preferably
ethanol, isopropanol, n-propanol and/or dipropylene glycol methyl
ether, in particular isopropanol and/or n-propanol.
[0103] Active ingredients with suitable dimensions may also be
occluded in pores in the activated porous carbon-based
coatings.
[0104] The loading with the active ingredient may be temporary,
i.e., the active ingredient may be released after implantation of
the medical device or the active ingredient may be permanently
immobilized in or on the carbon-based layer. In this way it is
possible to produce medical implants containing active ingredients
with static, dynamic or a combination of static and dynamic active
ingredient loads. This yields multifunctional coatings based on the
carbon-based layers produced according to this invention.
[0105] In static loading with active ingredients, the active
ingredients are essentially immobilized permanently in or on the
coating. Active ingredients used for this purpose include, but are
not limited to, inorganic substances, e.g., hydroxyl apatite (HAP),
fluorapatite, tricalcium phosphate (TCP), zinc and/or organic
substances such as peptides, proteins, carbohydrates such as
monosaccharides, oligosaccharides and polysaccharides, lipids,
phospholipids, steroids, lipoproteins, glycoproteins, glycolipids,
proteoglycans, DNA, RNA, signal peptides or antibodies and/or
antibody fragments, bioabsorbable polymers, e.g., polylactic acid,
chitosan as well as pharmacologically active substances or
substance mixtures, combinations thereof and the like.
[0106] In the case of dynamic active ingredient loading, it is
provided that the applied active ingredients will be released after
implantation of the medical device in the body. In this way the
coated implants may be used for therapeutic purposes, with the
active ingredients applied to the implant being released locally
and successively at the site of use of the implant. Active
ingredients that can be used in dynamic active ingredient loading
for the release of active ingredients include, but are not limited
to, for example, hydroxyl apatite (HAP), fluorapatite, tricalcium
phosphate (TCP), zinc and/or organic substances such as peptides,
proteins, carbohydrates such as monosaccharides, oligosaccharides
and polysaccharides, lipids, phospholipids, steroids, lipoproteins,
glycoproteins, glycolipids, proteoglycans, DNA, RNA, signal
peptides or antibodies and/or antibody fragments, bioabsorbable
polymers, e.g., polylactic acid, chitosan and the like as well as
pharmacologically active substances or substance mixtures.
[0107] Suitable pharmacologically active substances or substance
mixtures for static and/or dynamic loading of implantable medical
devices coated according to this invention include, but are not
limited to, active ingredients or active ingredient combinations
selected from heparin, synthetic heparin analogs (e.g.,
fondaparinux), hirudin, antithrombin III, drotrecogin alpha;
fibrinolytics such as alteplase, plasmin, lysokinases, factor XIIa,
prourokinase, urokinase, anistreplase, streptokinase; platelet
aggregation inhibitors such as acetylsalicylic acid [aspirin],
ticlopidine, clopidogrel, abciximab, dextrans; corticosteroids such
as alclometasone, amcinonide, augmented betamethasone,
beclomethasone, betamethasone, budesonide, cortisone, clobetasol,
clocortolone, desonide, desoximetasone, dexamethasone,
fluocinolone, fluocinonide, flurandrenolide, flunisolide,
fluticasone, halcinonide, halobetasol, hydrocortisone,
methylprednisolone, mometasone, prednicarbate, prednisone,
prednisolone, triamcinolone; so-called non-steroidal
anti-inflammatory drugs (NSAIDs) such as diclofenac, diflunisal,
etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin,
ketoprofen, ketorolac, meclofenamate, mefenamic acid, meloxicam,
nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac,
tolmetin, celecoxib, rofecoxib; cytostatics such as alkaloides and
podophyllum toxins such as vinblastine, vincristine; alkylating
agents such as nitrosoureas, nitrogen lost analogs; cytotoxic
antibiotics such as daunorubicin, doxorubicin and other
anthracyclines and related substances, bleomycin, mitomycin;
antimetabolites such as folic acid analogs, purine analogs or
pyrimidine analogs; paclitaxel, docetaxel, sirolimus; platinum
compounds such as carboplatin, cisplatin or oxaliplatin; amsacrin,
irinotecan, imatinib, topotecan, interferon-alpha 2a,
interferon-alpha 2b, hydroxycarbamide, miltefosine, pentostatin,
porfimer, aldesleukin, bexaroten, tretinoin; antiandrogens and
antiestrogens; antiarrythmics in particular class I antiarrhythmic
such as antiarrhythmics of the quinidine type, quinidine,
dysopyramide, ajmaline, prajmalium bitartrate, detajmium
bitartrate; antiarrhythmics of the lidocaine type, e.g., lidocaine,
mexiletin, phenytoin, tocainid; class Ic antiarrhythmics, e.g.,
propafenon, flecainid(acetate); class II antiarrhythmics
beta-receptor blockers such as metoprolol, esmolol, propranolol,
metoprolol, atenolol, oxprenolol; class III antiarrhythmics such as
amiodarone, sotalol; class IV antiarrhythmics such as diltiazem,
verapamil, gallopamil; other antiarrhythmics such as adenosine,
orciprenaline, ipratropium bromide; agents for stimulating
angiogenesis in the myocardium such as vascular endothelial growth
factor (VEGF), basic fibroblast growth factor (bFGF), non-viral
DNA, viral DNA, endothelial growth factors: FGF-1, FGF-2, VEGF,
TGF; antibiotics, monoclonal antibodies, anticalins; stem cells,
endothelial progenitor cells (EPC); digitalis glycosides, such as
acetyl digoxin/metildigoxin, digitoxin, digoxin; cardiac glycosides
such as ouabain, proscillaridin; antihypertensives such as CNS
active antiadrenergic substances, e.g., methyldopa, imidazoline
receptor agonists; calcium channel blockers of the dihydropyridine
type such as nifedipine, nitrendipine; ACE inhibitors:
quinaprilate, cilazapril, moexipril, trandolapril, spirapril,
imidapril, trandolapril; angiotensin II antagonists:
candesartancilexetil, valsartan, telmisartan, olmesartanmedoxomil,
eprosartan; peripherally active alpha-receptor blockers such as
prazosin, urapidil, doxazosin, bunazosin, terazosin, indoramin;
vasodilatators such as dihydralazine, diisopropylamine
dichloracetate, minoxidil, nitroprusside sodium; other
antihypertensives such as indapamide, co-dergocrine mesylate,
dihydroergotoxin methanessulfonate, cicletanin, bosentan,
fludrocortisone; phosphodiesterase inhibitors such as milrinon,
enoximon and antihypotensives such as in particular adrenergic and
dopaminergic substances such as dobutamine, epinephrine,
etilefrine, norfenefrine, norepinephrine, oxilofrine, dopamine,
midodrine, pholedrine, ameziniummetil; and partial adrenoceptor
agonists such as dihydroergotamine; fibronectin, polylysine,
ethylene vinyl acetate, inflammatory cytokines such as: TGF.beta.,
PDGF, VEGF, bFGF, TNF.alpha., NGF, GM-CSF, IGF-a, IL-1, IL-8, IL-6,
growth hormone; as well as adhesive substances such as
cyanoacrylates, beryllium, silica; and growth factors such as
erythropoetin, hormones such as corticotropins, gonadotropins,
somatropins, thyrotrophins, desmopressin, terlipressin, pxytocin,
cetrorelix, corticorelin, leuprorelin, triptorelin, gonadorelin,
ganirelix, buserelin, nafarelin, goserelin, as well as regulatory
peptides such as somatostatin, octreotid; bone and cartilage
stimulating peptides, bone morphogenetic proteins (BMPs), in
particulary recombinant BMPs, such as recombinant human BMP-2
(rhBMP-2), bisphosphonate (e.g., risedronate, pamidronate,
ibandronate, zoledronic acid, clodronsure, etidronsure, alendronic
acid, tiludronic acid), fluorides such as disodium fluorophosphate,
sodium fluoride; calcitonin, dihydrotachystyrol; growth factors and
cytokines such as epidermal growth factor (EGF), platelet-derived
growth factor (PDGF), fibroblast growth factors (FGFs),
transforming growth factors-b (TGFs-b), transforming growth
factor-a (TGF-a), erythropoietin (Epo), insulin-like growth
factor-I (IGF-I), insulin-like growth factor-II (IGF-II),
interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6),
interleukin-8 (IL-8), tumor necrosis factor-a (TNF-a), tumor
necrosis factor-b (TNF-b), interferon-g (INF-g), colony stimulating
factors (CSFs); monocyte chemotactic protein, fibroblast
stimulating factor 1, histamine, fibrin or fibrinogen,
endothelin-1, angiotensin II, collagens, bromocriptine,
methysergide, methotrexate, carbon tetrachloride, thioacetamide and
ethanol; as well as silver (ions), titanium dioxide, antibiotics
and anti-infective drugs such as in particular .beta.-lactam
antibiotics, e.g., .beta.-lactamase-sensitive penicillins such as
benzyl penicillins (penicillin G), phenoxymethylpenicillin
(penicillin V); .beta.-lactamase-resistent penicillins such as
aminopenicillins, e.g., amoxicillin, ampicillin, bacampicillin;
acylaminopenicillins such as mezlocillin, piperacillin;
carboxypenicillins, cephalosporins such as cefazoline, cefuroxim,
cefoxitin, cefotiam, cefaclor, cefadroxil, cefalexin, loracarbef,
cefixim, cefuroximaxetil, ceftibuten, cefpodoximproxetil,
cefpodoximproxetil; aztreonam, ertapenem, meropenem;
.beta.-lactamase inhibitors such as sulbactam,
sultamicillintosylate; tetracyclines such as doxycycline,
minocycline, tetracycline, chlorotetracycline, oxytetracycline;
aminoglycosides such as gentamicin, neomycin, streptomycin,
tobramycin, amikacin, netilmicin, paromomycin, framycetin,
spectinomycin; macrolide antibiotics such as azithromycin,
clarithromycin, erythromycin, roxithromycin, spiramycin, josamycin;
lincosamides such as clindamycin, lincomycin; gyrase inhibitors
such as fluoroquinolones, e.g., ciprofloxacin, ofloxacin,
moxifloxacin, norfloxacin, gatifloxacin, enoxacin, fleroxacin,
levofloxacin; quinolones such as pipemidic acid; sulfonamides,
trimethoprim, sulfadiazine, sulfalene; glycopeptide antibiotics
such as vancomycin, teicoplanin; polypeptide antibiotics such as
polymyxins, e.g., colistin, polymyxin-b, nitroimidazole derivates,
e.g., metronidazole, tinidazole; aminoquinolones such as
chloroquin, mefloquin, hydroxychloroquin; biguanids such as
proguanil; quinine alkaloids and diaminopyrimidines such as
pyrimethamine; amphenicols such as chloramphenicol; rifabutin,
dapson, fusidic acid, fosfomycin, nifuratel, telithromycin,
fusafungin, fosfomycin, pentamidine diisethionate, rifampicin,
taurolidin, atovaquon, linezolid; virus static such as aciclovir,
ganciclovir, famciclovir, foscarnet,
inosine-(dimepranol-4-acetamidobenzoate), valganciclovir,
valaciclovir, cidofovir, brivudin; antiretroviral active
ingredients (nucleoside analog reverse-transcriptase inhibitors and
derivatives) such as lamivudine, zalcitabine, didanosine,
zidovudin, tenofovir, stavudin, abacavir; non-nucleoside analog
reverse-transcriptase inhibitors: amprenavir, indinavir,
saquinavir, lopinavir, ritonavir, nelfinavir; amantadine,
ribavirine, zanamivir, oseltamivir and lamivudine, as well as any
combinations and mixtures thereof.
[0108] Especially preferred embodiments of the present invention
include, but are not limited to, coated vascular endoprostheses
(intraluminal endoprostheses) such as stents, coronary stents,
intravascular stents, peripheral stents and the like.
[0109] These can easily be functionalized in a biocompatible manner
by the method according to this invention, so that the residual
stenoses which frequently occur in percutaneous transluminal
angioplasty with traditional stents can be prevented.
[0110] By immobilizing suitable active ingredients on porous
carbon-based coatings, in particular paclitaxel, rapamycins or
dexamethasone, the local inflammation reaction in the tissue of the
vascular wall can be inhibited and/or suppressed by temporary local
release of these active ingredients. The use and efficacy of such
active ingredients is sufficiently well known according to the
state of the art, but the usability has been limited due to the
coating systems according to the state of the art, in particular
because of the inadequate load capacity which leads to inadequate
bioavailability, inadequate, i.e., incomplete release of these
active ingredients or intolerance between the coating system and
the active ingredient due to unwanted physical or chemical
interactions.
[0111] In preferred embodiments of the present invention, vitreous
carbon layers or composite layers with the addition of carbon black
particles with layer thicknesses between 80 nm and 10 .mu.m, pore
sizes from 5 nm to 1 .mu.m and porosities of 1% to 70% are produced
and activated, preferably by introducing fillers and then removing
them from the carbon layer or through the admixture of carbon black
particles having a spherical or ellipsoid or rod-shaped morphology
and a particle size of 10 nm to 200 nm, these particles creating a
porous matrix, so that active ingredients can be accommodated in a
sufficient amount. The surface of the stent implant may be
increased here up to 2000 m.sup.2/m.sup.3.
[0112] In preferred embodiments of this invention, by activation of
the carbon-based layer, e.g., with air at an elevated temperature,
the hydrophilic property of the coating can be increased, which in
turn additionally increases the biocompatibility, while on the
other hand making the layer better able to uptake active
ingredients, in particular hydrophilic active ingredients.
[0113] In especially preferred embodiments, stents, in particular
coronary stents and peripheral stents may be loaded with
pharmacologically active substances or substance mixtures or with
cells or cell cultures by the method according to this invention.
For example, the carbon-based stent surfaces may be finished with
the following active ingredients to locally suppress cell adhesion,
platelet aggregation, complement activation and/or inflammatory
tissue reactions or cell proliferation:
[0114] Heparin, synthetic heparin analogs (e.g., fondaparinux),
hirudin, antithrombin III, drotrecogin alpha, fibrinolytics
(alteplase, plasmin, lysokinases, factor XIIa, prourokinase,
urokinase, anistreplase, streptokinase), platelet aggregation
inhibitors (acetylsalicylic acid [aspirin], ticlopidine,
clopidogrel, abciximab, dextran), corticosteroids (alclometasone,
amcinonide, augmented betamethasone, beclomethasone, betamethasone,
budesonide, cortisone, clobetasol, clocortolone, desonide,
desoximetasone, dexamethasone, fluocinolone, fluocinonide,
flurandrenolide, flunisolide, fluticasone, halcinonide,
halobetasol, hydrocortisone, methylprednisolone, mometasone,
prednicarbate, prednisone, prednisolone, triamcinolone), so-called
non-steroidal anti-inflammatory drugs [NSAIDs] (diclofenac,
diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen,
indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid,
meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate,
sulindac, tolmetin, celecoxib, rofecoxib), cytostatics (alkaloids
and podophyllum toxins such as vinblastine, vincristine; alkylating
agents such as nitrosoureas, nitrogen lost analogs; cytotoxic
antibiotics such as daunorubicin, doxorubicin and other
anthracyclines and related substances, bleomycin, mitomycin;
antimetabolites such as folic acid, purine or pyrimidine analogs;
paclitaxel, docetaxel, sirolimus; platinum compounds such as
carboplatin, cisplatin or oxaliplatin; amsacrin, irinotecan,
imatinib, topotecan, interferon-alpha 2a, interferon-alpha 2b,
hydroxycarbamide, miltefosine, pentostatin, porfimer, aldesleukin,
bexaroten, tretinoin; antiandrogens and antiestrogens).
[0115] Stents activated according to this invention may be loaded
with any of the following for their systemic cardiological
effects:
[0116] Antiarrythmics, in particular class I antiarrhythmics
(antiarrhythmics of the quinidine type: quinidine, dysopyramide,
ajmaline, prajmalium bitartrate, detajmium bitartrate;
antiarrhythmics of the lidocaine type: lidocaine, mexiletin,
phenytoin, tocainid; class IC antiarrhythmics: propafenon,
flecainide (acetate)), class II antiarrhythmics (beta-receptor
blockers) (metoprolol, esmolol, propranolol, metoprolol, atenolol,
oxprenolol), class III antiarrhythmics (amiodaron, sotalol), calss
IV antiarrhythmics (diltiazem, verapamil, gallopamil), other
antiarrhythmics such as adenosine, orciprenaline, ipratropium
bromide; stimulation of angiogenesis in the myocardium: vascular
endothelial growth factor (VEGF), basic fibroblast growth factor
(bFGF), nonviral DNA, viral DNA, endothelial growth factors: FGF-1,
FGF-2, VEGF, TGF; antibodies, monoclonal antibodies, anticalins;
stem cells, endothelial progenitor cells (EPC). Other cardiac
agents include, but are not limited to,: digitalis glycosides
(acetyldigoxin/metildigoxin- , digitoxin, digoxin), other cardiac
glycosides (ouabain, proscillaridin). In addition the stents may be
loaded antihypertensives (CNS active antiadrenergic substances;
methyldopa, imidazoline receptor agonists; calcium channel blocker
of the dihydropyridine type such as nifedipine, nitrendipine; ACE
inhibitors: quinaprilat, cilazapril, moexipril, trandolapril,
spirapril, imidapril, trandolapril; angiotensin II antagonists:
candesartancilexetil, valsartan, telmisartan, olmesartanmedoxomil,
eprosartan; peripheral acting alpha-receptor blockers: prazosin,
urapidil, doxazosin, bunazosin, terazosin, indoramin; vasodilators:
dihydralazine, diisopropylamine dichloracetate, minoxidil,
nitroprusside sodium), other antihypertensives such as indapamide,
co-dergocrine mesylate, dihydroergotoxin methane sulfonate,
cicletanin, bosentan. In addition, phosphodiesterase inhibitors
(milrinon, enoximon) and antihypotensives, here in particular
adrenergic and dopaminergic substances (dobutamine, epinephrine,
etilefrine, norfenefrine, norepinephrine, oxilofrine, dopamine,
midodrine, pholedrine, amezinium metil), partial adrenoceptor
agonists (dihydroergotamine), and finally other antihypotensives
such as fludrocortisone may also be used.
[0117] To increase tissue adhesion, in particular in the case of
peripheral stents, components of the extracellular matrix,
fibronectin, polylysine, ethylene vinyl acetate, inflammatory
cytokines such as: TGF.beta., PDGF, VEGF, bFGF, TNF.alpha., NGF,
GM-CSF, IGF-a, IL-1, IL-8, IL-6, growth hormones and adhesive
substances such as cyanoacrylates, beryllium or silica may also be
used.
[0118] Other substances suitable for here and having a systemic
and/or local effect include, but are not limited to, growth factors
and erythropoetin.
[0119] Hormones may also be provided in the stent coatings such as
corticotropins, gonadotropins, somatropin, thyrotrophin,
desmopressin, terlipressin, oxytocin, cetrorelix, corticorelin,
leuprorelin, triptorelin, gonadorelin, ganirelix, buserelin,
nafarelin, goserelin, and regulatory peptides such as somatostatin
and/or octreotid.
[0120] Other embodiments provide for functionalization by loading
the carbon surfaces with cells, e.g., with pluripotent stem cells,
endothelial cells or connective tissue cells which may be obtained
from organisms, cultured from cell cultures in the laboratory or
modified by genetic engineering.
[0121] For example in a special embodiment, vascular implants
provided with activated carbon layers may be loaded with
endothelial cell cultures by first using them as a substrate in a
bioreactor and/or as a culturing and carrier system for cell
cultures. Suitable methods here include, but are not limited to,
those described in German Patent DE 103 35 131, i.e.,
PCT/EP04/00077, the disclosure content is herewith included.
[0122] For example, inventive nanoporous activated carbon layers
with a surface area of 200 to 3000 m.sup.2/m.sup.3 can be loaded
with endothelial cells after culturing, in which case the possible
cell densities range from 10.sup.1 to 10.sup.16 cells/mL layer
volume, preferably 10.sup.3 to 10.sup.12 cells/mL.
[0123] In the case of surgical and orthopedic implants, it may be
advantageous to activate the implants with one or more carbon-based
layers so that the layers are macroporous. Suitable pore sizes are
in the range of 0.1 to 1000 .mu.m, preferably 1 to 400 .mu.m to
support better integration of the implants by incorporation into
the surrounding cell tissue or bone tissue.
[0124] For orthopedic and nonorthopedic implants as well as heart
valves or synthetic heart parts functionalized according to this
invention, if they are to be loaded with active ingredients, the
same active ingredients may be used as those listed for the stent
applications described above or local suppression of cell adhesion,
platelet aggregation, complement activation and/or inflammatory
tissue reaction or cell proliferation.
[0125] Furthermore, for stimulation of tissue growth in particular
in the case of orthopedic implants, the following active
ingredients may be used to improve implant integration: bone and
cartilage stimulating peptides, bone morphogenetic proteins (BMPs),
in particular recombinant BMPs (e.g., recombinant human BMP-2
(rhBMP-2)), bisphosphonates (e.g., risedronate, pamidronate,
ibandronate, zoledronic acid, clodronic acid, etidronic acid,
alendronic acid, tiludronic acid), fluorides (disodium
fluorophosphate, sodium fluoride); calcitonin, dihydrotachystyrene.
Then all the growth factors and cytokines may be used (epidermal
growth factor (EGF), platelet-derived growth factor (PDGF),
fibroblast growth factors (FGFs), transforming growth factors-b
(TGFs-b), transforming growth factor-a (TGF-a), erythropoietin
(Epo), insulin-like growth factor I (IGF-I), insulin-like growth
factor II (IGF-II), interleukin-1 (IL-1), interleukin-2 (IL-2),
interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-a
(TNF-a), tumor necrosis factor-b (TNF-b), Interferon-g (INF-g),
colony stimulating factors (CSFs)). In addition to the inflammatory
cytokines mentioned above, other adhesion-promoting and
integration-promoting substances include, but are not limited to,
the monocyte chemotactic protein, fibroblast stimulating factor 1,
histamine, fibrin or fibrinogen, endothelin-1, angiotensin II,
collagens, bromocriptine, methysergide, methotrexate, carbon
tetrachloride, thioacetamide, ethanol.
[0126] In addition, the implants, stents and the like that have
been activated according to this invention may also be provided
with antibacterial-antiinfectious coatings or impregnation instead
of or in addition to pharmaceutical drugs, in which case the
following substances or substance mixtures may be used: silver
(ions), titanium dioxide, antibiotics and antiinfective agents. In
particular these include, but are not limited to, beta-lactam
antibiotics (.beta.-lactam antibiotics: .beta.-lactamase-sensitive
penicillins such as benzyl penicillins (penicillin G),
phenoxymethyl penicillin (penicillin V));
.beta.-lactamase-resistant penicillins such as aminopenicillins,
e.g., amoxicillin, ampicillin, bacampicillin; acylaminopenicillins
such as mezlocillin, piperacillin; carboxypenicillins,
cephalosporins (cefazolin, cefuroxim, cefoxitin, cefotiam,
cefaclor, cefadroxil, cefalexin, loracarbef, cefixim,
cefuroximaxetil, ceftibuten, cefpodoximproxetil,
cefpodoximproxetil) or other such as aztreonam, ertapenem,
meropenem. Other antibiotics that may be used include, but are not
limited to, .beta.-lactamase inhibitors (sulbactam,
sultamicillintosylate), tetracyclins (doxycyclin, minocyclin,
tetracyclin, chlortetracyclin, oxytetracyclin), aminoglycosides
(gentamicin, neomycin, streptomycin, tobramycin, amikacin,
netilmicin, paromomycin, framycetin, spectinomycin), macrolide
antibiotics (azithromycin, clarithromycin, erythromycin,
roxithromycin, spiramycin, josamycin), lincosamids (clindamycin,
lincomycin), gyrase inhibitors (fluoroquinolones such as
ciprofloxacin, ofloxacin, moxifloxacin, norfloxacin, gatifloxacin,
enoxacin, fleroxacin, levofloxacin; other quinolones such as
pipemidic acid), sulfonamids and trimethoprim (sulfadiazin,
sulfalen, trimethoprim), glycopeptide antibiotics (vancomycin,
teicoplanin), polypeptide antibiotics (polymyxins such as colistin,
polymyxin-b), nitroimidazole derivates (metronidazole, tinidazole),
aminoquinolones (chloroquin, mefloquin, hydroxychloroquin),
biguanids (proguanil), quinine alkaloids and diaminopyrimidines
(pyrimethamine), amphenicols (chloramphenicol) and other
antibiotics (rifabutin, dapson, fusidinic acid, fosfomycin,
nifuratel, telithromycin, fusafungin, fosfomycin, pentamidine
diisethionate, rifampicin, taurolidine, atovaquone, linezolide).
Examples of virus statics that can be mentioned include, but are
not limited to, aciclovir, ganciclovir, famciclovir, foscarnet,
inosine-(dimepranol-4-acetamidobenzoate), valganciclovir,
valaciclovir, cidofovir, brivudin. This also include, but are not
limited to, antiretroviral active ingredients (nucleoside analog
reverse-transcriptase inhibitors and derivatives: lamivudine,
zalcitabine, didanosine, zidovudin, tenofovir, stavudin, abacavir;
non-nucleoside analog reverse-transcriptase inhibitors: amprenavir,
indinavir, saquinavir, lopinavir, ritonavir, nelfinavir) and other
virustatics such as amantadin, ribavirin, zanamivir, oseltamivir,
lamivudin.
[0127] In especially preferred embodiments of the present
invention, the inventive implants may be suitably modified in their
chemical or physical properties with carbon-based layers before or
after loading of the active ingredient by using other agents, e.g.,
to modify the hydrophilicity, hydrophobicity, electric
conductivity, adhesion or other surface properties. Substances that
can be used for this purpose include, but are not limited to,
biodegradable or non-degradable polymers such as for the
biodegradable polymers: collagens, albumin, gelatin, hyaluronic
acid, starch, cellulose (methyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, carboxymethyl cellulose phthalate;
also casein, dextrans, polysaccharides, fibrinogen,
poly(D,L-lactides), poly(D,L-lactide-co-glycolide),
poly(glycolides), poly(hydroxybutylates), poly(alkyl carbonates),
poly(ortho esters), polyesters, poly(hydroxyvaleric acid),
polydioxanones, poly(ethylene terephtalate), poly(malic acid),
poly(tartronic acid), polyanhydride, polyphosphohazenes, poly(amino
acids) and all their copolymers.
[0128] The non-biodegradable polymers include, but are not limited
to,: poly(ethylene vinyl acetates), silicones, acrylic polymers
such as polyacrylic acid, polymethyl acrylic acid, polyacryl
cyanoacrylate; polyethylenes, polypropylenes, polyamides,
polyurethanes, poly(ester urethanes), poly(ether urethanes),
poly(ester ureas), polyethers such as polyethylene oxide,
polypropylene oxide, pluronics, polytetramethylene glycol; vinyl
polymers such as polyvinylpyrrolidones, poly(vinyl alcohols),
poly(vinyl acetate phthalate); parylenes.
[0129] It is true in general that polymers with anionic properties
(e.g., alginate, carrageenan, carboxymethyl cellulose) or cationic
(e.g., chitosan, poly-L-lysine, etc.) or both properties
(phosphorylcholine) can be produced.
[0130] These polymers can be applied to the surface of the implants
and may cover them partially or entirely.
[0131] To modify the release properties of inventive implants
containing one or more active ingredients, specific pH-dependent or
temperature-dependent release properties can be achieved by
applying additional polymers, for example. Examples of pH-sensitive
polymers include, but are not limited to, poly(acrylic acid) and
derivatives thereof, e.g., homopolymers such as
poly(aminocarboxylic acid), poly(acrylic acid), poly(methyl acrylic
acid) and copolymers thereof. This is also true of polysaccharides
such as cellulose acetate phthalate, hydroxypropylmethyl cellulose
phthalate, hydroxypropylmethyl cellulose succinate, cellulose
acetate trimellitate and chitosan. Thermally sensitive polymers
include, but are not limited to, for example
poly(N-isopropylacrylamide-co-sodium
acrylate-co-n-N-alkylacrylamide),
poly(N-methyl-N-n-propylacrylamide),
poly(N-methyl-N-isopropylacrylamide)- ,
poly(N-n-propylmethacrylamide), poly(N-isopropylacrylamide),
poly(N,n-diethylacrylamide), poly(N-isopropylmethacrylamide),
poly(N-cyclopropylacrylamide), poly(N-ethyl-acrylamide),
poly(N-ethyl-methyacrylamide), poly(N-methyl-N-ethylacrylamide),
poly(N-cyclopropylacrylamide). Other polymers with thermogel
characteristics include, but are not limited to, hydroxypropyl
cellulose, methyl cellulose, hydroxypropylmethyl cellulose,
ethylhydroxyethyl cellulose and pluronics such as F-127, L-122,
L-92, L-81, L-61.
[0132] The active ingredients may be adsorbed in the pores of the
carbon-based layer (covalently, non-covalently) in which case their
release can be controlled primarily through pore size and pore
geometry. Additional modifications of the porous chemical layer by
chemical modification (anionic, cationic) make it possible to
modify the release, e.g., as a function of pH. The release of
carriers that contain active ingredient also constitutes another
application namely microcapsules, liposomes, nanocapsules,
nanoparticles, micelles, synthetic phospholipids, gas dispersions,
emulsions, microemulsions, nanospheres etc., which are adsorbed in
the pores of the carbon layer and are then released
therapeutically. By additional covalent or non-covalent
modification of the carbon layer, the pores can be occluded so that
bioactive ingredients are protected. Possibilities include, but are
not limited to, the above-mentioned polysaccharides, lipids, etc.,
but also the polymers mentioned above.
[0133] Therefore, in the additional coating of the porous
carbon-based layers produced according to this invention with
additional layers, a distinction may be made between physical
barriers such as inert biodegradable substances (poly-L-lysine,
fibronectin, chitosan, heparin, etc.) and biologically active
barriers. The latter may be sterically hindering molecules which
are physiologically bioactivated and which permit the release of
active ingredients and/or their vehicles. Examples include, but are
not limited to, enzymes which mediate the release, activate
biologically active substances or bind inactive coatings and lead
to exposure of active ingredients. All this specific mechanisms and
properties listed here can be applied to the primary carbon layer
as well as additional layers applied thereto.
[0134] By applying the release-modifying polymer layers mentioned
above and/or by adapting the pore structure of the carbon-based
layer, it is possible to control the release of the active
ingredients from the implant in a wide range. achievable release
times include, but are not limited to, up to twelve hours, up to
one or more years, preferably 24 hours, 48 hours, 96 hours, one
week, two weeks, one month, three months.
[0135] The inventive implants may also be loaded with live cells or
microorganisms in special applications and may be functionalized in
this way. These cells or microorganisms may form colonies in
suitably porous carbon-based layers and the implant colonized in
this way may be provided with a suitable membrane coating which is
permeable for nutrients and active ingredients produced by cells or
microorganisms but is not permeable for the cells themselves. Thus
the cells or microorganisms can be supplied from the organism
through the membrane coating.
[0136] For example, by using the inventive technology in this way,
it is possible to produce implants which contain insulin-producing
cells that produce and release insulin according to the prevailing
glucose level after being implanted in the body.
[0137] The invention is further described by the following numbered
paragraphs:
[0138] 1. A method for producing medical implants having
functionalized surfaces comprising the following steps:
[0139] a) providing a medical implant with at least one
carbon-based layer on at least part of the surface of the
implant;
[0140] b) activating the carbon-based layer by creating
porosity;
[0141] c) functionalizing the activated carbon-based layer.
[0142] 2. The method according to paragraph 1, characterized in
that the carbon-based layer is selected from pyrolytically produced
carbon, vapor-deposited carbon, carbon applied by CVD, PVD or
sputtering, metal carbides, metal carbonitrides, metal oxynitrides
or metal oxycarbides as well as any desired combinations
thereof.
[0143] 3. The method according to paragraph 1 or 2, characterized
in that the implant consists of a material which is selected from
carbon, carbon composite material, carbon fibers, ceramic, glass,
plastics, metals, alloys, bone, stone or minerals.
[0144] 4. The method according to any one of the preceding
paragraphs, characterized in that the implant is selected from
medical or therapeutic implants such as vascular endoprostheses,
stents, coronary stents, peripheral stents, surgical or orthopedic
implants, bone prostheses or joint prostheses, artificial hearts,
artificial heart valves, subcutaneous and/or intramuscular
implants.
[0145] 5. The method according to any one of the preceding
paragraphs, characterized in that activation of the carbon-based
layer is performed with suitable oxidizing agents and/or reducing
agents.
[0146] 6. The method according to any one of the preceding
paragraphs, characterized in that the carbon-based layer is
activated by oxidation with air, oxygen, nitrous oxide, and/or
oxidizing acids, optionally at an elevated temperature.
[0147] 7. The method according to any one of the preceding
paragraphs, characterized in that the activation is performed by
abrasion in an aqueous ultrasonic bath with the addition of
alumina, silicates and/or aluminates.
[0148] 8. The method according to any one of the preceding
paragraphs, characterized in that activation causes the
carbon-based layer to become porous, preferably macroporous with
pore diameters in the range of 0.1 to 1000 mm, optionally also by
prestructuring the substrate.
[0149] 9. The method according to any one of the preceding
paragraphs, characterized in that activation causes the
carbon-based layer to become nanoporous.
[0150] 10. The method according to any one of the preceding
paragraphs, characterized in that the activate porous carbon-based
layer is subsequently compressed and/or sealed by CVD and/or CVI of
volatile organic substances.
[0151] 11. The method according to any one of the preceding
paragraphs, characterized in that the functionalization of the
activated carbon-based layer comprises loading the layer with at
least one substance selected from pharmacological active
ingredients, linkers, microorganisms, plant or animal cells
including human cells or cell cultures and tissue, minerals, salts,
metals, synthetic or natural polymers, proteins, peptides, amino
acids, solvents, ions, cations, in particular metal cations such as
cobalt, nickel, copper, zinc cations, antibodies, calmodulin,
chitin, cellulose, sugars, amino acids, glutathione, streptavidin,
Strep-Tactin or other mutants or S protein, dextrans, as well as
their derivatives, mixtures and combinations.
[0152] 12. The method according to any one of the preceding
paragraphs, characterized in that the functionalization is
performed by adsorption of substances corresponding to affinity
tags in and/or on the carbon-based layer, whereby the corresponding
substances are selected so that they can enter into a bond with the
affinity tags.
[0153] 13. The method according to paragraph 11 or 12,
characterized in that the substance(s) is/are applied to and/or
immobilized on the carbon-based layer by adsorption, absorption,
physisorption, chemisorption, electrostatic covalent bonding or
non-covalent bonding.
[0154] 14. The method according to paragraph 11, characterized in
that the at least one substance is essentially permanently
immobilized on the carbon-based layer(s).
[0155] 15. The method according to paragraph 11, characterized in
that the at least one substance applied to the carbon-based layer,
in particular a pharmacological active ingredient, can be released
from the layer in a controlled manner.
[0156] 16. The method according to paragraph 15, characterized in
that the pharmacologically active substances are incorporated into
microcapsules, liposomes, nanocapsules, nanoparticles, micelles,
synthetic phospholipids, gas dispersions, emulsions, microemulsions
or nanospheres which are adsorbed in the pores or on the surface of
the carbon-based layer and can then be released
therapeutically.
[0157] 17. The method according to any one of paragraphs 14 through
16, characterized in that the a coating which influences the
release of the active ingredient is also applied, selected from
pH-sensitive and/or temperature-sensitive polymers and/or
biologically active barriers such as enzymes.
[0158] 18. The method according to any one of the preceding
paragraphs, characterized in that the functionalization includes
applying biodegradable and/or absorbable polymers such as collagen,
albumin, gelatin, hyaluronic acid, starch, celluloses such as
methyl cellulose hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, carboxymethylcellulose phthalate; casein, dextrans,
polysaccharides, fibrinogen, poly(D,L-lactide),
poly(D,L-lactide-co-glycolide), poly(glycolide),
poly(hydroxybutylate), poly(alkyl carbonate), poly(orthoester),
polyester, poly(hydroxyvaleric acid), polydioxanone, poly(ethylene
terephtalate), poly(malic acid), poly(tartronic acid),
polyanhydrides, polyphosphazenes, poly(amino acids) and their
copolymers.
[0159] 19. The method according to any one of the preceding
paragraphs, characterized in that the functionalization includes
applying non-biodegradable and/or non-absorbable polymers such as
poly(ethylene vinyl acetate), silicones, acrylic polymers such as
polyacrylic acid, polymethyl acrylic acid, polyacryl cyanoacrylate;
polyethylenes, polypropylenes, polyamides, polyurethanes,
poly(ester urethanes), poly(ether urethanes), poly(ester ureas),
polyethers, polyethylene oxide, polypropylene oxide, pluronics,
polytetramethylene glycol; vinyl polymers such as
polyvinylpyrrolidones, poly(vinyl alcohols), poly(vinyl acetate
phthalate) as well as their copolymers.
[0160] 20. An implant having a functionalized surface producible
according to any one of the preceding paragraphs.
[0161] 21. The implants according to paragraph 20, characterized in
that it is made of metals such as stainless steel, titanium,
tantalum, platinum, gold, palladium, alloys, in particular memory
alloys such as nitinol or nickel titanium alloys or carbon fibers,
solid carbon material or carbon composites.
[0162] 22. The implant according to any one of paragraphs 20 or 21
comprising multiple carbon-based layers optionally loaded with
active ingredient.
[0163] 23. A device according to any one of paragraphs 20 though
22, also comprising anionic or cationic or amphoteric coatings
selected from alginate, carrageenan, carboxymethyl cellulose,
poly(meth)acrylates, chitosan, poly-L-lysines and/or
phosphorylcholine.
[0164] 24. A stent coated with an active ingredient according to
any one of paragraphs 20 through 23.
[0165] 25. A heart valve coated with an active ingredient according
to any one of paragraphs 20 through 23.
[0166] 26. The implant according to any one of paragraphs 20
through 23 in the form of an orthopedic bone prosthesis or joint
prosthesis, a bone substitute or a vertebral substitute in the
thoracic or lumbar region of the spinal column.
[0167] 27. An active ingredient depot with controlled release that
can be used subcutaneously and/or intramuscularly according to any
one of paragraphs 20 through 23.
[0168] 28. The implant according to any one of paragraphs 20
through 27, comprising applied and/or incorporated microorganisms,
viral vectors or cells or tissue.
[0169] 29. A use of an implant according to paragraph 28 for
producing a therapeutic effect or for increasing the
bioavailability of the implant after implantation of the implant in
the human body.
[0170] Having thus described in detail preferred embodiments of the
present invention, it is to be understood that the invention
defined by the above paragraphs is not to be limited to particular
details set forth in the above description as many apparent
variations thereof are possible without departing from the spirit
or scope of the present invention.
* * * * *